RESUMO
Background: Streptococcus pneumoniae is the most common bacterium that causes community-acquired pneumonia (CAP) in children. The rate of S. pneumoniae resistance to antibiotics is increasing, particularly in patients with severe CAP. Therefore, the level of antibiotic resistance of S. pneumoniae causing severe CAP in Vietnamese children requires regular monitoring. Methods: This was a cross-sectional descriptive study. Nasopharyngeal aspiration specimens from children were cultured, isolated, and examined for S. pneumoniae. Bacterial strains were assessed for antimicrobial susceptibility, and the minimum inhibitory concentration (MIC) was determined. Results: Eighty-nine strains of S. pneumoniae were isolated from 239 children with severe CAP. The majority of isolates were completely non-susceptible to penicillin (1.1% intermediate, 98.9% resistant) and highly resistant to erythromycin (96.6%) and clarithromycin (88.8%); the rate of resistance to ceftriaxone was 16.9%, with the proportion of intermediate resistance at 46.0%; 100% of strains were susceptible to vancomycin and linezolid. For most antibiotics, MIC50 and MIC90 were equal to the resistance threshold according to the Clinical and Laboratory Standards Institute 2021; penicillin had an eight-fold increase in MIC90 (64 mg/L) and ceftriaxone had a 1.5-fold increase in MIC90 (6 mg/L). Conclusion: Streptococcus pneumoniae isolates described in this study were resistant to many antibiotics. Penicillin should not be the first-line antibiotic of choice, and ceftriaxone at an enhanced dose should be used instead.
Assuntos
Antibacterianos , Resistência Microbiana a Medicamentos , Pneumonia Pneumocócica , Pneumonia , Streptococcus pneumoniae , Criança , Humanos , Antibacterianos/farmacologia , Ceftriaxona , Estudos Transversais , Penicilinas , População do Sudeste Asiático , Streptococcus pneumoniae/genética , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/genética , Pneumonia Pneumocócica/fisiopatologia , Pneumonia Pneumocócica/virologiaRESUMO
Streptococcus pneumoniae is an asymptomatic colonizer of the nasopharynx, but it is also one of the most important bacterial pathogens of humans, causing a wide range of mild to life-threatening diseases. The basis of the pneumococcal transition from a commensal to a parasitic lifestyle is not fully understood. We hypothesize that exposure to host catecholamine stress hormones is important for this transition. In this study, we demonstrated that pneumococci preexposed to a hormone released during stress, norepinephrine (NE), have an increased capacity to translocate from the nasopharynx into the lungs compared to untreated pneumococci. Examination of NE-treated pneumococci revealed major alterations in metabolic profiles, cell associations, capsule synthesis, and cell size. By systemically mutating all 12 two-component and 1 orphan regulatory systems, we also identified a unique genetic regulatory circuit involved in pneumococcal recognition and responsiveness to human stress hormones. IMPORTANCE Microbes acquire unique lifestyles under different environmental conditions. Although this is a widespread occurrence, our knowledge of the importance of various host signals and their impact on microbial behavior is not clear despite the therapeutic value of this knowledge. We discovered that catecholamine stress hormones are the host signals that trigger the passage of Streptococcus pneumoniae from a commensal to a parasitic state. We identify that stress hormone treatment of this microbe leads to reductions in cell size and capsule synthesis and renders it more able to migrate from the nasopharynx into the lungs in a mouse model of infection. The microbe requires the TCS09 protein for the recognition and processing of stress hormone signals. Our work has particular clinical significance as catecholamines are abundant in upper respiratory fluids as well as being administered therapeutically to reduce inflammation in ventilated patients, which may explain why intubation in the critically ill is a recognized risk factor for the development of pneumococcal pneumonia.
Assuntos
Translocação Bacteriana , Pulmão/microbiologia , Pneumonia Pneumocócica/microbiologia , Streptococcus pneumoniae/fisiologia , Animais , Feminino , Humanos , Camundongos , Nasofaringe/microbiologia , Norepinefrina/metabolismo , Pneumonia Pneumocócica/metabolismo , Pneumonia Pneumocócica/fisiopatologia , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/crescimento & desenvolvimento , Estresse FisiológicoRESUMO
Streptococcus pneumoniae is the leading cause of hospital community-acquired pneumonia. Patients with pneumococcal pneumonia may develop complicated parapneumonic effusions or empyema that can lead to pleural organization and subsequent fibrosis. The pathogenesis of pleural organization and scarification involves complex interactions between the components of the immune system, coagulation, and fibrinolysis. EPCR (endothelial protein C receptor) is a critical component of the protein C anticoagulant pathway. The present study was performed to evaluate the role of EPCR in the pathogenesis of S. pneumoniae infection-induced pleural thickening and fibrosis. Our studies show that the pleural mesothelium expresses EPCR. Intrapleural instillation of S. pneumoniae impairs lung compliance and lung volume in wild-type and EPCR-overexpressing mice but not in EPCR-deficient mice. Intrapleural S. pneumoniae infection induces pleural thickening in wild-type mice. Pleural thickening is more pronounced in EPCR-overexpressing mice, whereas it is reduced in EPCR-deficient mice. Markers of mesomesenchymal transition are increased in the visceral pleura of S. pneumoniae-infected wild-type and EPCR-overexpressing mice but not in EPCR-deficient mice. The lungs of wild-type and EPCR-overexpressing mice administered intrapleural S. pneumoniae showed increased infiltration of macrophages and neutrophils, which was significantly reduced in EPCR-deficient mice. An analysis of bacterial burden in the pleural lavage, the lungs, and blood revealed a significantly lower bacterial burden in EPCR-deficient mice compared with wild-type and EPCR-overexpressing mice. Overall, our data provide strong evidence that EPCR deficiency protects against S. pneumoniae infection-induced impairment of lung function and pleural remodeling.
Assuntos
Receptor de Proteína C Endotelial/deficiência , Pulmão/metabolismo , Pleura/metabolismo , Derrame Pleural/metabolismo , Pleurisia/metabolismo , Pneumonia Pneumocócica/metabolismo , Streptococcus pneumoniae/patogenicidade , Animais , Carga Bacteriana , Células Cultivadas , Modelos Animais de Doenças , Receptor de Proteína C Endotelial/genética , Feminino , Fibrose , Interações Hospedeiro-Patógeno , Humanos , Pulmão/microbiologia , Pulmão/patologia , Pulmão/fisiopatologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Pleura/microbiologia , Pleura/patologia , Derrame Pleural/microbiologia , Derrame Pleural/patologia , Derrame Pleural/fisiopatologia , Pleurisia/microbiologia , Pleurisia/patologia , Pleurisia/fisiopatologia , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/patologia , Pneumonia Pneumocócica/fisiopatologiaRESUMO
BACKGROUND: Streptococcus pneumoniae (Pnc) serotypes differ in invasive potential. We examined whether community-acquired alveolar pneumonia (CAAP) in children carrying commonly recognized pneumonia invasive pneumococcal serotypes ([PnIST] 1, 5, 7F, 14, and 19A) differs from CAAP in children carrying less invasive serotypes (non-PnIST) or no Pnc (Pnc-neg). METHODS: Children <5 years, visiting the only regional Pediatric Emergency Room, with radiologically proven CAAP were enrolled. Nasopharyngeal cultures were processed for pneumococcal isolation and serotyping. Clinical and demographic characteristics were recorded. The study was conducted before pneumococcal conjugate vaccine implementation in Israel. RESULTS: A total of 1423 CAAP episodes were recorded: PnIST, 300 (21.1%); non-PnIST, 591 (41.5%); and Pnc-neg, 532 (37.4%). After adjustment for age, ethnicity, seasonality, and previous antibiotics, the following variables were positively associated with PnIST carriage compared with both groups: temperature ≥39°C, peripheral white blood cell count ≥20 000/mm3, C-reactive protein ≥70.0 mg/L, and serum sodium <135 mEq/L. Lower oxygen saturation, viral detection, and comorbidities were negatively associated with Pn-IST carriage (odds ratios, <1.0). Differences between non-PnIST carriers and Pnc-neg groups were smaller or nonsignificant. CONCLUSIONS: Young children with CAAP carrying common PnIST had a lower proportion of comorbidities, hypoxemia, and viral detection and had more intense systemic inflammatory response than those carrying non-PnIST or not carrying Pnc.
Assuntos
Portador Sadio/imunologia , Nasofaringe/microbiologia , Pneumonia Pneumocócica/fisiopatologia , Sorogrupo , Streptococcus pneumoniae/imunologia , Pré-Escolar , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/fisiopatologia , Feminino , Humanos , Lactente , Israel , Masculino , Vacinas Pneumocócicas/imunologia , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/prevenção & controle , Estudos Prospectivos , Sorotipagem , Vacinas Conjugadas/imunologiaRESUMO
"Science means constantly walking a tight rope" Heinrich Rohrer, physicist, 1933. Community-acquired pneumonia (CAP) is the leading cause of death from infectious disease worldwide and disproportionately affects older adults and children. In high-income countries, pneumonia is one of the most common reasons for hospitalisation and (when recurrent) is associated with a risk of developing chronic pulmonary conditions in adulthood. Pneumococcal pneumonia is particularly prevalent in older adults, and here, pneumonia is still associated with significant mortality despite the widespread use of pneumococcal vaccination in middleand high-income countries and a low prevalence of resistant organisms. In older adults, 11% of pneumonia survivors are readmitted within months of discharge, often with a further pneumonia episode and with worse outcomes. In children, recurrent pneumonia occurs in approximately 10% of survivors and therefore is a significant cause of healthcare use. Current antibiotic trials focus on short-term outcomes and increasingly shorter courses of antibiotic therapy. However, the high requirement for further treatment for recurrent pneumonia questions the effectiveness of current strategies, and there is increasing global concern about our reliance on antibiotics to treat infections. Novel therapeutic targets and approaches are needed to improve outcomes. Neutrophils are the most abundant immune cell and among the first responders to infection. Appropriate neutrophil responses are crucial to host defence, as evidenced by the poor outcomes seen in neutropenia. Neutrophils from older adults appear to be dysfunctional, displaying a reduced ability to target infected or inflamed tissue, poor phagocytic responses and a reduced capacity to release neutrophil extracellular traps (NETs); this occurs in health, but responses are further diminished during infection and particularly during sepsis, where a reduced response to granulocyte colony-stimulating factor (G-CSF) inhibits the release of immature neutrophils from the bone marrow. Of note, neutrophil responses are similar in preterm infants. Here, the storage pool is decreased, neutrophils are less able to degranulate, have a reduced migratory capacity and are less able to release NETs. Less is known about neutrophil function from older children, but theoretically, impaired functions might increase susceptibility to infections. Targeting these blunted responses may offer a new paradigm for treating CAP, but modifying neutrophil behaviour is challenging; reducing their numbers or inhibiting their function is associated with poor clinical outcomes from infection. Uncontrolled activation and degranulation can cause significant host tissue damage. Any neutrophil-based intervention must walk the tightrope described by Heinrich Rohrer, facilitating necessary phagocytic functions while preventing bystander host damage, and this is a significant challenge which this review will explore.
Assuntos
Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/epidemiologia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Neutropenia/epidemiologia , Pneumonia Pneumocócica/epidemiologia , Adulto , Fatores Etários , Idoso , Antibacterianos/uso terapêutico , Causas de Morte , Criança , Pré-Escolar , Infecções Comunitárias Adquiridas/fisiopatologia , Feminino , Avaliação Geriátrica/métodos , Humanos , Incidência , Lactente , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutropenia/fisiopatologia , Neutrófilos/imunologia , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/fisiopatologia , Prognóstico , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , Estados UnidosRESUMO
Bacterial pneumonia remains a leading cause of morbidity and mortality worldwide. A defining feature of pneumonia is lung injury, leading to protracted suffering and vulnerability long after bacterial clearance. Little is known about which cells are damaged during bacterial pneumonia and if the regenerative process can be harnessed to promote tissue repair and host recovery. Here, we show that infection of mice with Streptococcus pneumoniae (Sp) caused substantial damage to alveolar epithelial cells (AEC), followed by a slow process of regeneration. Concurrent with AEC regeneration, the expression of miRNA-302 is elevated in AEC. Treatment of Sp-infected mice with miRNA-302 mimics improved lung functions, host recovery, and survival. miRNA-302 mediated its therapeutic effects, not by inhibiting apoptosis and preventing damage, but by promoting proliferation of local epithelial progenitor cells to regenerate AEC. These results demonstrate the ability of microRNA-based therapy to promote AEC regeneration and enhance host recovery from bacterial pneumonia.
Assuntos
MicroRNAs/farmacologia , Pneumonia Pneumocócica/fisiopatologia , Regeneração/efeitos dos fármacos , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Pneumonia Pneumocócica/metabolismo , RNA de Cadeia Dupla/genética , RNA de Cadeia Dupla/metabolismo , RNA de Cadeia Dupla/farmacologia , Streptococcus pneumoniaeRESUMO
AIM: The aim was to analyze the epidemiological, microbiological and clinical characteristics of patients with complicated pneumococcal pneumonia with pleural effusion (PE) or empyema. METHOD: Prospective study in three Catalan hospitals in persons aged <18 years diagnosed with complicated pneumonia with PE or empyema with isolation of Streptococcus pneumoniae in blood or pleural fluid by culture or real-time PCR between January 2012 and June 2016. Patients were divided into <2 years and 2-17 years age groups. Epidemiological, microbiological, and clinical data of patients were compared annually in both groups. PCV13 vaccination coverage increased from 48.2% in 2012 to 74.5% in 2015. RESULTS: We included 143 patients. The incidence of pneumococcal pneumonia was 6.83 cases × 10-5 persons/year in cases with PE or empyema and 2.09 cases × 10-5 person-years in cases without (rate ratio [RR]: 3.27; 2.25-4.86; P < 0.001). Empyema was more frequent than PE (79.7% vs 20.3%, P < 0.005). Of 143 cases studied, 93 (65.0%, P < 0.001) were diagnosed by real-time-PCR, 43 (30.1%) by culture and RT-PCR and 7 (4.9%) by culture only. PCV13 serotypes were more frequent in complicated than in uncomplicated pneumonia (116/142, 81.7% vs 27/45, 60.0%; P = 0.003), especially serotype 1 (41/142, 28.9% vs 6/45, 13.3%, P : 0.036). From 2012 to 2015 there was a significant reduction in serotype 1 (16/43, 37.2% vs 3/27, 11.1%, P = 0.026), and a trend to an increase in non-PCV13 serotypes (6/43, 14% vs 9/27, 33.3%, P = 0.054). CONCLUSIONS: A directly proportional relationship was observed between the reduction in pneumonia complicated with PE or empyema and a significant reduction in PCV13 serotypes, especially serotype 1, coinciding with increased PCV13 coverage.
Assuntos
Empiema Pleural/epidemiologia , Derrame Pleural/epidemiologia , Pneumonia Pneumocócica/epidemiologia , Adolescente , Criança , Pré-Escolar , Empiema Pleural/etiologia , Empiema Pleural/fisiopatologia , Feminino , Humanos , Incidência , Lactente , Masculino , Derrame Pleural/etiologia , Derrame Pleural/fisiopatologia , Vacinas Pneumocócicas/uso terapêutico , Pneumonia Pneumocócica/complicações , Pneumonia Pneumocócica/fisiopatologia , Pneumonia Pneumocócica/prevenção & controle , Estudos Prospectivos , Sorogrupo , Espanha/epidemiologia , Streptococcus pneumoniaeRESUMO
INTRODUCTION: Few studies have prospectively evaluated recovery process and long-term consequences of pleural space infections. OBJECTIVE: To evaluate clinical, pulmonary, and diaphragmatic function and radiological outcome in patients hospitalized with pleural empyema. MATERIAL AND METHODS: Previously healthy patients from 6 to 16 years were enrolled. Demographic, clinical, and treatment data were registered. At hospital discharge, and every 30 days or until normalization, patients underwent a clinical evaluation, diaphragmatic ultrasound, and lung function testing. Chest radiographs were performed at subsequent visits only if abnormalities persisted. RESULTS: Thirty patients were included. Nineteen (63%) were male, with an age of (mean ± SD) 9.7 ± 3.2 years, and body mass index (mean ± SD) 18.6 ± 3. Twelve patients (40%) were treated with chest tube drainage only, 12 (40%) exclusively with surgery, and 6 (20%) completed treatment with surgery due to an ineffective chest tube drainage. At hospital discharge, 26 (87%) of patients had abnormal breath sounds at the site of infection, 28 (93%) had a spirometric restrictive pattern, 19 (63%) diaphragmatic motion impairment, and 29 (97%) presented radiological involvement of pleural space, mainly pleural thickening. All patients had recovered diaphragmatic motion and were asymptomatic at 90- and 120-day follow-up control, respectively. Then, with a great individual variability, radiological findings, and lung function returned to normal at 60 days (range 30-180) and 90 days (range 30-180) after hospital discharge, respectively. CONCLUSION: Patients with pleural empyema had a complete and progressive recovery, with initial clinical and diaphragmatic motion normalization followed by radiological and lung function recovery.
Assuntos
Diafragma/diagnóstico por imagem , Drenagem/métodos , Empiema Pleural/terapia , Pneumonia Pneumocócica/terapia , Infecções Estafilocócicas/terapia , Toracentese/métodos , Toracotomia/métodos , Adolescente , Tubos Torácicos , Criança , Diafragma/fisiopatologia , Empiema Pleural/diagnóstico por imagem , Empiema Pleural/fisiopatologia , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Pneumonia Pneumocócica/diagnóstico por imagem , Pneumonia Pneumocócica/fisiopatologia , Radiografia Torácica , Testes de Função Respiratória , Espirometria , Infecções Estafilocócicas/diagnóstico por imagem , Infecções Estafilocócicas/fisiopatologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , UltrassonografiaRESUMO
A 34-year-old HIV-positive man with a history of chronic substance abuse was admitted with dual infection of Streptococcus pneumoniae and Listeria monocytogenes. Combined bacteraemia with S. pneumoniae and L. monocytogenes is very rare. To the best of our knowledge, this is the first such case documented at our institution and in South Africa. Ampicillin should be added to antibiotic regimens to improve patient outcome if L. monocytogenes infection is suspected. Co-infections that occur with L. monocytogenes may have conflicting antibiotic treatment options. This case report emphasises the need for a good relationship between the local microbiology pathologist and physician to select appropriate antibiotic treatment before definitive results are available.
Assuntos
Ampicilina/administração & dosagem , Ceftriaxona/administração & dosagem , Soropositividade para HIV/sangue , Listeria monocytogenes/isolamento & purificação , Listeriose , Pneumonia Pneumocócica , Streptococcus pneumoniae/isolamento & purificação , Adulto , Anemia/diagnóstico , Anemia/terapia , Antibacterianos/administração & dosagem , Transfusão de Sangue/métodos , Contagem de Linfócito CD4/métodos , Coinfecção/diagnóstico , Coinfecção/imunologia , Coinfecção/fisiopatologia , Coinfecção/terapia , Evolução Fatal , HIV/imunologia , Humanos , Listeriose/diagnóstico , Listeriose/imunologia , Listeriose/fisiopatologia , Listeriose/terapia , Masculino , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/etiologia , Pneumonia Pneumocócica/diagnóstico , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/fisiopatologia , Pneumonia Pneumocócica/terapia , Respiração Artificial/métodosRESUMO
RATIONALE: During pneumonia, pathogen-host interaction evokes inflammation and lung barrier dysfunction. Tie2 activation by angiopoietin-1 reduces, whereas Tie2 blockade by angiopoietin-2 increases, inflammation and permeability during sepsis. The role of angiopoietin-1/-2 in pneumonia remains unidentified. OBJECTIVES: To investigate the prognostic and pathogenic impact of angiopoietins in regulating pulmonary vascular barrier function and inflammation in bacterial pneumonia. METHODS: Serum angiopoietin levels were quantified in pneumonia patients of two independent cohorts (n = 148, n = 395). Human postmortem lung tissue, pneumolysin- or angiopoietin-2-stimulated endothelial cells, isolated perfused and ventilated mouse lungs, and mice with pneumococcal pneumonia were investigated. MEASUREMENTS AND MAIN RESULTS: In patients with pneumonia, decreased serum angiopoietin-1 and increased angiopoietin-2 levels were observed as compared with healthy subjects. Higher angiopoietin-2 serum levels were found in patients with community-acquired pneumonia who died within 28 days of diagnosis compared with survivors. Receiver operating characteristic analysis revealed improved prognostic accuracy of CURB-65 for 28-day survival, intensive care treatment, and length of hospital stay if combined with angiopoietin-2 serum levels. In vitro, pneumolysin enhanced endothelial angiopoietin-2 release, angiopoietin-2 increased endothelial permeability, and angiopoietin-1 reduced pneumolysin-evoked endothelial permeability. Ventilated and perfused lungs of mice with angiopoietin-2 knockdown showed reduced permeability on pneumolysin stimulation. Increased pulmonary angiopoietin-2 and reduced angiopoietin-1 mRNA expression were observed in Streptococcus pneumoniae-infected mice. Finally, angiopoietin-1 therapy reduced inflammation and permeability in murine pneumonia. CONCLUSIONS: These data suggest a central role of angiopoietin-1/-2 in pneumonia-evoked inflammation and permeability. Increased angiopoietin-2 serum levels predicted mortality and length of hospital stay, and angiopoietin-1 may provide a therapeutic target for severe pneumonia.
Assuntos
Angiopoietina-1/uso terapêutico , Angiopoietina-2/uso terapêutico , Células Endoteliais/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Inflamação/fisiopatologia , Pulmão/efeitos dos fármacos , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/fisiopatologia , Angiopoietina-1/sangue , Angiopoietina-2/sangue , Humanos , PrognósticoRESUMO
Patients with COPD and other chronic respiratory diseases are especially vulnerable to viral and bacterial pulmonary infections, which are major causes of exacerbations, hospitalization, disease progression, and mortality in COPD patients. Effective vaccines could reduce the burden of respiratory infections and acute exacerbations in COPD patients, but what is the evidence for this? This article reviews and discusses the existing evidence for pneumococcal vaccination efficacy and its changing role in patients with chronic respiratory diseases, especially COPD. Specifically, the recent Community-Acquired Pneumonia Immunization Trial in Adults (CAPITA) showed the efficacy of pneumococcal conjugate vaccine in older adults, many of whom had additional risk factors for pneumococcal disease, including chronic lung diseases. Taken together, the evidence suggests that pneumococcal and influenza vaccinations can prevent community-acquired pneumonia and acute exacerbations in COPD patients, while pneumococcal vaccination early in the course of COPD could help maintain stable health status. Despite the need to prevent pulmonary infections in patients with chronic respiratory diseases and evidence for the efficacy of pneumococcal conjugate vaccine, pneumococcal vaccine coverage and awareness are low and need to be improved. Respiratory physicians need to communicate the benefits of vaccination more effectively to their patients who suffer from chronic respiratory diseases.
Assuntos
Pulmão/microbiologia , Vacinas Pneumocócicas/administração & dosagem , Pneumonia Pneumocócica/prevenção & controle , Doença Pulmonar Obstrutiva Crônica/microbiologia , Vacinação , Progressão da Doença , Nível de Saúde , Humanos , Pulmão/fisiopatologia , Vacinas Pneumocócicas/efeitos adversos , Pneumonia Pneumocócica/diagnóstico , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Resultado do Tratamento , Vacinação/efeitos adversosRESUMO
Pneumococcal pneumonia is a leading cause of mortality worldwide. The inflammatory response to bacteria is necessary to control infection, but it may also contribute to tissue damage. Phosphodiesterase-4 inhibitors, such as rolipram (ROL), effectively reduce inflammation. Here, we examined the impact of ROL in a pneumococcal pneumonia murine model. Mice were infected intranasally with 10(5)-10(6) CFU of Streptococcus pneumoniae, treated with ROL in a prophylactic or therapeutic schedule in combination, or not, with the antibiotic ceftriaxone. Inflammation and bacteria counts were assessed, and ex vivo phagocytosis assays were performed. ROL treatment during S. pneumoniae infection decreased neutrophil recruitment into lungs and airways and reduced lung injury. Prophylactic ROL treatment also decreased cytokine levels in the airways. Although modulation of inflammation by ROL ameliorated pneumonia, bacteria burden was not reduced. On the other hand, antibiotic therapy reduced bacteria without reducing neutrophil infiltration, cytokine level, or lung injury. Combined ROL and ceftriaxone treatment decreased lethality rates and was more efficient in reducing inflammation, by increasing proresolving protein annexin A1 (AnxA1) expression, and bacterial burden by enhancing phagocytosis. Lack of AnxA1 increased inflammation and lethality induced by pneumococcal infection. These data show that immunomodulatory effects of phosphodiesterase-4 inhibitors are useful during severe pneumococcal pneumonia and suggest their potential benefit as adjunctive therapy during infectious diseases.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/enzimologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Pneumonia Pneumocócica/complicações , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/enzimologia , Pneumonia/complicações , Animais , Anexina A1/metabolismo , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ceftriaxona/farmacologia , Ceftriaxona/uso terapêutico , Pulmão/microbiologia , Pulmão/patologia , Lesão Pulmonar/complicações , Lesão Pulmonar/fisiopatologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Fagocitose/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Pneumonia/fisiopatologia , Pneumonia Pneumocócica/fisiopatologia , Testes de Função Respiratória , Rolipram/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/fisiologiaRESUMO
BACKGROUND: Lymphatic pump treatment (LPT) is a technique used by osteopathic physicians as an adjunct to antibiotics for patients with respiratory tract infections, and previous studies have demonstrated that LPT reduces bacterial load in the lungs of rats with pneumonia. Currently, it is unknown whether LPT affects drug effcacy. OBJECTIVE: To determine whether the combination of antibiotics and LPT would reduce bacterial load in the lungs of rats with acute pneumonia. METHODS: Rats were infected intranasally with 5×107 colony-forming units (CFU) of Streptococcus pneumoniae. At 24, 48, and 72 hours after infection, the rats received no therapy (control), 4 minutes of sham therapy, or 4 minutes of LPT, followed by subcutaneous injection of 40 mg/kg of levofoxacin or sterile phosphate-buffered saline. At 48, 72, and 96 hours after infection, the spleens and lungs were collected, and S pneumoniae CFU were enumerated. Blood was analyzed for a complete blood cell count and leukocyte differential count. RESULTS: At 48 and 72 hours after infection, no statistically significant differences in pulmonary CFU were found between control, sham therapy, or LPT when phosphate-buffered saline was administered; however, the reduction in CFU was statistically significant in all rats given levofoxacin. The combination of sham therapy and levofoxacin decreased bacterial load at 72 and 96 hours after infection, and LPT and levofoxacin significantly reduced CFU compared with sham therapy and levofoxacin at both time points (P<.05). Colony-forming units were not detected in the spleens at any time. No statistically significant differences in hematologic findings between any treatment groups were found at any time point measured. CONCLUSION: The results suggest that 3 applications of LPT induces an additional protective mechanism when combined with levofoxacin and support its use as an adjunctive therapy for the management of pneumonia; however, the mechanism responsible for this protection is unclear.
Assuntos
Antibacterianos/uso terapêutico , Pneumonia Pneumocócica/terapia , Ducto Torácico/fisiopatologia , Animais , Modelos Animais de Doenças , Masculino , Osteopatia , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Streptococcus pneumoniae/isolamento & purificaçãoRESUMO
BACKGROUND: Serious lower respiratory tract infections (SLRTIs), especially Streptococcus pneumoniae (SP)-related pneumonia cause considerable morbidity and mortality. Chest imaging, sputum and blood culture are not routinely obtained by general practitioners (GPs). Antibiotic therapy is usually started empirically. The BinaxNOW® and Urine Antigen Detection (UAD) assays have been developed respectively to detect a common antigen from all pneumococcal strains and the 13 pneumococcal serotypes present in the vaccine Prevenar 13® (PCV13). METHODS: OPUS-B was a multicentre, prospective, case-control, observational study of patients with SLRTI in primary care in Belgium, conducted during two winter seasons (2011-2013). A urine sample was collected at baseline for the urine assays. GPs were blinded to the results. All patients with a positive BinaxNOW® test and twice as much randomly selected BinaxNOW® negative patients were followed up. Recorded data included: socio-demographics, medical history, vaccination history, clinical symptoms, CRB-65 score, treatments, hospitalization, blood cultures, healthcare use, EQ-5D score. The objectives were to evaluate the percentage of SP SLRTI within the total number of SLRTIs, to assess the percentage of SP serotypes and to compare the burden of disease between pneumococcal and non-pneumococcal SLRTIs. RESULTS: There were 26 patients with a BinaxNOW® positive test and 518 patients with a BinaxNOW® negative test. The proportion of pneumococcal SLRTI was 4.8 % (95 % CI: 3.1 %-7.2 %). Sixty-eight percent of positive cases showed serotypes represented in PCV13. In the BinaxNOW-positive patients, women were more numerous, there was less exposure to young children, seasonal influenza vaccination was less frequent, COPD was more frequent, the body temperature and the number of breaths per minute were higher, the systolic blood pressure was lower, the frequency of sputum, infiltrate, chest pain, muscle ache, confusion/disorientation, diarrhoea, pneumonia and exacerbations of COPD was more frequent, EQ-5D index and VAS scale were lower, the number of visits to the GP, of working days lost and of days patients needed assistance were higher. CONCLUSIONS: SP was responsible for approximately 5 % of SLRTIs observed in primary care in Belgium. Pneumococcal infection was associated with a significant increase in morbidity. Sixty-eight percent of serotypes causing SLRTI were potentially preventable by PCV13.
Assuntos
Antibacterianos/uso terapêutico , Vacinas Pneumocócicas/uso terapêutico , Pneumonia Pneumocócica , Atenção Primária à Saúde , Streptococcus pneumoniae , Adulto , Idoso , Bélgica/epidemiologia , Estudos de Casos e Controles , Feminino , Clínicos Gerais/normas , Necessidades e Demandas de Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Pneumocócica/diagnóstico , Pneumonia Pneumocócica/epidemiologia , Pneumonia Pneumocócica/fisiopatologia , Pneumonia Pneumocócica/terapia , Serviços Preventivos de Saúde/normas , Atenção Primária à Saúde/métodos , Atenção Primária à Saúde/normas , Sorotipagem/métodos , Streptococcus pneumoniae/imunologia , Streptococcus pneumoniae/isolamento & purificação , Vacinas Conjugadas/uso terapêuticoRESUMO
BACKGROUND: Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide. During pneumococcal pneumonia, the human airway epithelium is exposed to large amounts of H2O2 as a product of host and pathogen oxidative metabolism. Airway cells are known to be highly vulnerable to oxidant damage, but the pathophysiology of oxidative stress induced by S. pneumoniae and the role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant systems of the host are not well characterized. METHODS: For gluthation/gluthathion disulfide analysis BEAS-2B cells, primary broncho-epithelial cells (pBEC), explanted human lung tissue and mouse lungs were infected with different S. pneumoniae strains (D39, A66, R6x, H2O2/pneumolysin/LytA- deficient mutants of R6x). Cell death was proven by LDH assay and cell viability by IL-8 ELISA. The translocation of Nrf2 and the expression of catalase were shown via Western blot. The binding of Nrf2 at the catalase promoter was analyzed by ChIP. RESULTS: We observed a significant induction of oxidative stress induced by S. pneumoniae in vivo, ex vivo, and in vitro. Upon stimulation, the oxidant-responsive transcription factor Nrf2 was activated, and catalase was upregulated via Nrf2. The pneumococci-induced oxidative stress was independent of S. pneumoniae-derived H2O2 and pneumolysin but depended on the pneumococcal autolysin LytA. The Nrf2 inducer resveratrol, as opposed to catalase, reversed oxidative stress in lung epithelial cells. CONCLUSIONS: These observations indicate a H2O2-independent induction of oxidative stress in lung epithelial cells via the release of bacterial factors of S. pneumoniae. Resveratrol might be an option for prevention of acute lung injury and inflammatory responses observed in pneumococcal pneumonia.
Assuntos
Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Pneumonia Pneumocócica/imunologia , Estilbenos/farmacologia , Streptococcus pneumoniae/imunologia , Animais , Antioxidantes/farmacologia , Autólise , Proteínas de Bactérias/metabolismo , Linhagem Celular , Sobrevivência Celular , Células Epiteliais/imunologia , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Interleucina-8/metabolismo , Pulmão/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/fisiopatologia , Resveratrol , Estreptolisinas/metabolismoRESUMO
BACKGROUND: The incidence of necrotizing pneumococcal pneumonia has increased during the past 2 decades. We hypothesized that increased pneumococcal load or augmented inflammatory cytokine production might lead to destructive pneumococcal lung disease. METHODS: This study enrolled prospectively 0- to 18-year-old children with a diagnosis of community-acquired pneumonia with pleural effusion admitted to 6 medical centers from March 2010 to April 2012. Children were diagnosed with pneumococcal empyema if the pleural fluid tested positive for quantitative pneumococcal (lytA) detection by real-time polymerase chain reaction. Pneumococcal empyema cases were further divided into 4 groups according to necrosis severity: (0) nonnecrosis, (1) mild necrosis, (2) cavitation and (3) bronchopleural fistula. Nasopharyngeal and pleural pneumococcal load, as well as levels of proinflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-8), Th1-(IL-2, IFN-γ), Th2-(IL-4, IL-10) and Th17-cytokines (IL-17), in the pleural fluid was measured. RESULTS: Serotypes 19A and 3 accounted for 69.4% and 12.5%, respectively, of 72 cases of pneumococcal empyema. Pleural pneumococcal load was significantly higher in serotypes 19A and 3 infection than in the other strains causing infection (P = 0.006). There was a correlation between nasopharyngeal and pleural pneumococcal load (ρ = 0.35; P = 0.05). In multivariate ordinal logistic regression analysis, pleural pneumococcal load (adjusted odds ratio: 1.79; 95% confidence interval: 1.03-3.06) and IL-8 (adjusted odds ratio: 2.64; 95% confidence interval: 1.21-5.75) were independent factors associated with the severity of lung necrosis. CONCLUSIONS: Evolution of Streptococcus pneumoniae toward increased fitness in their interaction with host and exaggerated IL-8 expression may be responsible for the increase of necrotizing pneumococcal pneumonia.
Assuntos
Necrose/epidemiologia , Necrose/microbiologia , Pneumonia Pneumocócica/epidemiologia , Pneumonia Pneumocócica/microbiologia , Streptococcus pneumoniae/patogenicidade , Análise de Variância , Carga Bacteriana , Citocinas/sangue , Empiema , Humanos , Incidência , Pulmão/diagnóstico por imagem , Pulmão/microbiologia , Pulmão/patologia , Nasofaringe/microbiologia , Necrose/fisiopatologia , Pneumonia Pneumocócica/fisiopatologia , Estudos Prospectivos , RadiografiaRESUMO
In the developing world, vitamin A (VA) deficiency is endemic in populations that are also at great risk of morbidity and mortality because of pneumococcal pneumonia and enteric infections. To better understand how lung and gastrointestinal pathogens affect VA status, we assessed VA concentrations in serum, lung, and liver during an invasive pneumonia infection induced by Streptococcus pneumoniae serotype 3, and a noninvasive gut infection induced by Citrobacter rodentium, in vitamin A-adequate (VAA) and vitamin A-deficient (VAD) mice. For pneumonia infection, mice were immunized with pneumococcal polysaccharide serotype 3 (PPS3), or not (infected-control), 5 d prior to intranasal inoculation with S. pneumoniae. Two days post-inoculation, immunization was protective against systemic infection regardless of VA status as PPS3 immunization decreased bacteremia compared with infected-control mice (P < 0.05). Retinol concentrations in the lung were higher in infected-control VAA mice (15.7 nmol/g: P < 0.05) compared with PPS3-immunized mice (8.23 nmol/g), but this was not associated with increased lung bacterial burden. VAA mice had reduced severity of C. rodentium-induced gut infection as measured by fecal bacterial shedding compared with VAD mice (P < 0.05). Liver retinol and retinyl ester concentrations in VAA mice decreased at the peak of infection (retinol, 8.1 nmol/g; retinyl esters, 985 nmol/g; P < 0.05, compared with uninfected mice; retinol, 29.5 nmol/g; retinyl esters, 1730 nmol/g), whereas tissue VA concentrations were low in VAD mice during both infections. Colonic mucin gene expression was also depressed at peak infection compared with uninfected mice (P < 0.05). Overall, pneumonia had less effect on VA status than gastrointestinal infection, predominantly owing to reduced hepatic VA storage at the peak of gut infection.
Assuntos
Infecções por Enterobacteriaceae/fisiopatologia , Gastroenteropatias/fisiopatologia , Fígado/química , Pulmão/química , Pneumonia Pneumocócica/fisiopatologia , Vitamina A/química , Animais , Citrobacter rodentium , Feminino , Gastroenteropatias/microbiologia , Trato Gastrointestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Streptococcus pneumoniae , Vacinação , Deficiência de Vitamina A/microbiologiaRESUMO
BACKGROUND: Osteopathic physicians utilize manual medicine techniques called lymphatic pump techniques (LPT) to improve lymphatic flow and enhance immunity. Clinical studies report that LPT enhances antibody responses to bacterial vaccines, shortens duration of cough in patients with respiratory disease, and shortens the duration of intravenous antibiotic therapy and hospital stay in patients with pneumonia. The purpose of this study was to identify if thoracic LPT (Th-LPT) or abdominal LPT (Ab-LPT) would reduce Streptococcus pneumoniae colony-forming units (CFU) in the lungs of rats with acute pneumonia. METHODS AND RESULTS: Rats were nasally infected with S. pneumoniae and received either control, sham, Ab-LPT, or Th-LPT once daily for 3 consecutive days. On day 4 post-infection, lungs were removed and bacteria were enumerated. Three daily applications of either Ab-LPT or Th-LPT were able to significantly (p<0.05) reduce the numbers of pulmonary bacteria compared to control and sham. There were no significant differences in the percentage or concentration of leukocytes in blood between groups, suggesting neither Ab-LPT nor Th-LPT release leukocytes into blood circulation. CONCLUSIONS: Our data demonstrate that LPT may protect against pneumonia by inhibiting bacterial growth in the lung; however, the mechanism of protection is unclear. Once these mechanisms are understood, LPT can be optimally applied to patients with pneumonia, which may substantially reduce morbidity, mortality, and frequency of hospitalization.
Assuntos
Pulmão/fisiopatologia , Sistema Linfático/fisiopatologia , Osteopatia/métodos , Pneumonia Pneumocócica/fisiopatologia , Streptococcus pneumoniae/crescimento & desenvolvimento , Abdome/fisiopatologia , Animais , Carga Bacteriana , Interações Hospedeiro-Patógeno , Contagem de Leucócitos , Pulmão/microbiologia , Sistema Linfático/microbiologia , Masculino , Pneumonia Pneumocócica/microbiologia , Ratos , Ratos Endogâmicos F344 , Streptococcus pneumoniae/fisiologia , Ducto Torácico/fisiopatologia , Fatores de TempoRESUMO
Sepsis is characterized by a generalized inflammatory response and organ failure, associated with mitochondrial dysfunction. Hydrogen sulfide donor NaHS has anti-inflammatory properties, is able to reduce metabolism and can preserve mitochondrial morphology and function. Rats were challenged with live Streptococcus pneumonia or saline and infused with NaHS (36 µmol/kg/h) or vehicle. Lung and kidney injury markers were measured as well as mitochondrial function, viability and biogenesis. Infusion of NaHS reduced heart rate and body temperature, indicative of a hypo-metabolic state. NaHS infusion reduced sepsis-related lung and kidney injury, while host defense remained intact, as reflected by unchanged bacterial outgrowth. The reduction in organ injury was associated with a reversal of a fall in active oxidative phosphorylation with a concomitant decrease in ATP levels and ATP/ADP ratio. Preservation of mitochondrial respiration was associated with increased mitochondrial expression of α-tubulin and protein kinase C-ε, which acts as regulators of respiration. Mitochondrial damage was decreased by NaHS, as suggested by a reduction in mitochondrial DNA leakage in the lung. Also, NaHS treatment was associated with upregulation of peroxisome proliferator-activated receptor-γ coactivator 1α, with a subsequent increase in transcription of mitochondrial respiratory subunits. These findings indicate that NaHS reduces organ injury in pneumosepsis, possibly via preservation of oxidative phosphorylation and thereby ATP synthesis as well as by promoting mitochondrial biogenesis. Further studies on the involvement of mitochondria in sepsis are required.
Assuntos
Anti-Inflamatórios/farmacologia , Metabolismo Energético , Lesão Pulmonar/prevenção & controle , Pneumonia Pneumocócica/tratamento farmacológico , Sulfetos/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lesão Pulmonar/metabolismo , Lesão Pulmonar/microbiologia , Mitocôndrias/metabolismo , Renovação Mitocondrial/efeitos dos fármacos , Oxirredução , Pneumonia Pneumocócica/metabolismo , Pneumonia Pneumocócica/fisiopatologia , Proteína Quinase C-épsilon/metabolismo , Ratos , Ratos Sprague-Dawley , Sepse , Sulfetos/uso terapêutico , Tubulina (Proteína)/metabolismo , Regulação para CimaRESUMO
The acute-phase response is characteristic of perhaps all infections, including bacterial pneumonia. In conjunction with the acute-phase response, additional biological pathways are induced in the liver and are dependent on the transcription factors STAT3 and NF-κB, but these responses are poorly understood. Here, we demonstrate that pneumococcal pneumonia and other severe infections increase expression of multiple components of the cellular secretory machinery in the mouse liver, including the endoplasmic reticulum (ER) translocon complex, which mediates protein translation into the ER, and the coat protein complexes (COPI and COPII), which mediate vesicular transport of proteins to and from the ER. Hepatocyte-specific mutation of STAT3 prevented the induction of these secretory pathways during pneumonia, with similar results observed following pharmacological activation of ER stress by using tunicamycin. These findings implicate STAT3 in the unfolded protein response and suggest that STAT3-dependent optimization of secretion may apply broadly. Pneumonia also stimulated the binding of phosphorylated STAT3 to promoter regions of secretion-related genes in the liver, supporting a direct role for STAT3 in their transcription. Altogether, these results identify a novel function of STAT3 during the acute-phase response, namely, the induction of secretory machinery in hepatocytes. This may facilitate the processing and delivery of newly synthesized loads of acute-phase proteins, enhancing innate immunity and preventing liver injury during infection.